Anaplasia

Hyperplasia, Hypertrophy, Carcinoma, Sarcoma

Hyperplasia: an increase in the number of cells in an organ or tissue, which usually leads to an increase in the size of the tissue or organ

Hypertrophy: an increase in the size of cells, leading to an increase in the size of the organ

HyperplasiaThis can be physiological or pathological.

Physiological hyperplasia can be divided into hormonal hyperplasia and compensatory hyperplasia.

Hormonal hyperplasia increases the functional capacity of a tissue when needed, for example there is proliferation of the glandular epithelium of the female breast at puberty and during pregnancy.

Compensatory hyperplasia is an increase in tissue mass after damage or resection eg regeneration of the liver.

Physiological hyperplasia is due to an increase in the level of locally produced growth factors. The new cells can be derived from proliferation of the local population of cells or from differentiation of stem cells. [Stem cells = ]

Pathological hyperplasia is most commonly caused by excessive hormonal stimulation or growth factors acting on target cells. A common example is benign prostatic hyperplasia (BPH) caused by responses to testosterone. Pathological hyperplasia is abnormal but the process remains controlled and it regresses if the hormonal stimulus is taken away. This is what makes BPH different from prostatic cancer. However cancer is more likely to arise in tissues undergoing pathological hyperplasia.

HypertrophyThere are no new cells in hypertrophy, the cells are just larger. The cells are larger due to synthesis of more structural components. For example we mentioned muscle hypertrophy where the diameter of the muscle fibre increases due to larger amounts of myofibrils, mitochondria and sarcoplasmic reticulum.

Hypertrophy tends to occur on its own if the cell is non-dividing, whereas cells capable of division can respond to stress by both hypertrophy and hyperplasia.

This can be physiological or pathological. It can be caused by increased functional demand eg muscle or by hormones eg uterus during pregnancy. (The uterus increases in size during pregnancy due to both hypertrophy and hyperplasia.)Cardiac muscle can undergo hypertrophy as a response to long term increased demands on the heart. This could be due to hypertension, valvular disease or anaemia. Eventually cardiac hypertrophy reaches a limit beyond which muscle mass can no longer compensate for the increased burden and cardiac failure results. At this stage a number of degenerative changes occur in the myofibrils with lysis and loss of contractile elements. Myocyte death can occur either by apoptosis or necrosis.

There is a limit to the size of hypertrophied cells at which they can function effectively. This could be due to limitation in vascular supply to the cells or failure of the mitochondria to support the cell, or changes in protein synthesis or breakdown, or changes in the cytoskeleton.

MetaplasiaDefinition: A reversible change in which one adult cell type is replaced by another adult cell type.It may represent an adaptation of one cell type to another cell type that is more likely to survive in the environment. The most common example of epithelial metaplasia is the transformation of columnar to squamous epithelium in response to chronic irritation. This can occur in the respiratory tract of cigarette smokers. The squamous epithelium can survive, whereas columnar epithelium cannot in this environment. However, by undergoing metaplasia, an important protective mechanism of the columnar cells, mucous secretion, is lost. Metaplasia is usually an undesirable change, and if the influences that have led to it remain in the future, malignant change within the metaplastic epithelium may occur. For example, the common form of cancer in the lung is composed of squamous cells, which arise in areas of metaplasia of the normal columnar epithelium into squamous epithelium. Metaplasia of squamous to columnar cells occurs in a condition called Barretts oesophagus. This occurs in reflux disease, where the acid creates a similar environment in the oesophagus to the stomach. The oesophageal squamous epithelium undergoes metaplasia to form columnar cells similar to those in the stomach. Cancers can arise in these areas, which are typically glandular adenocarcinomas.Metaplasia is not the result of the change of phenotype of an already differentiated cell. Instead, it is due to a reprogramming of stem cells or undifferentiated mesenchymal cells within normal tissue. In metaplastic change, these precursor cells differentiate along a new pathway.

NeoplasiaNeoplasia = the process of new growth.A new growth is called a neoplasm.Cancer is the common term for all malignant tumours (neoplasms).Tumour originally meant swelling, but now means the same as neoplasm.A neoplasm is an abnormal mass of tissue, the growth of which exceeds, and is uncoordinated with, that of normal tissue, and persists in the same excessive manner after the cessation of the stimuli which evoked the change.A tumour is due to genetic changes within one cell. These genetic changes allow this single cell to undergo excessive and unregulated proliferation. This proliferation becomes autonomous (independent of physiological growth stimuli). The tumour therefore continues to grow, even when the initiating stimulus is removed.

Differentiation refers to the extent to which neoplastic cells resemble normal cells of the same type. Lack of differentiation is called anaplasia. Malignant neoplasms composed of undifferentiated cells are said to be anaplastic. Features of anaplasia include:Pleomorphism - variation in size and shape of cells and their nucleiAbnormal nuclear morphology – large nuclei with unusual shapeMitoses – higher number of mitoses due to rapid turnoverLoss of polarity of tissue – tumour cells grow in a disorganized way, without normal tissue architecture.Cells of benign tumours are almost always well differentiated and resemble their cells of origin. Malignant neoplasms may be well differentiated or undifferentiated, but some loss of differentiation is always present.

DysplasiaDysplasia is disordered growthThere is loss of uniformity of individual cells and a loss of their tissue architecture. When dysplastic changes are marked, they involve the entire thickness of the epithelium. It is considered a pre-invasive neoplasm, also called carcinoma in situ. However, dysplasia does not necessarily always progress to cancer.

Tumour GrowthThere are 4 phases of tumour gtowth1. Malignant change within one cell (transformation)2. Proliferation of transformed cells3. Local invasion4. Distant metastases

Control of the cell cycle is deranged in the transformed cell. Tumour cells cycle more readily, and without the usual restraints. There is an excess of cell production over cell loss. In general the growth rate of tumours correlates with a lack of differentiation. Most malignant tumours grow more rapidly than benign tumours.

Local invasionNearly all benign tumours grow as a single expansile mass, and remain localized at their site of origin. They do not have the capacity to infiltrate, invade or metastasise to distant sites, unlike malignant tumours.As benign tumours grow slowly, they usually develop a ring of connective tissue (fibrous capsule) that separates it from the normal tissue. The capsule doesn’t prevent tumour growth, but keeps it as a discreet mass that can be surgically removed (enucleated).Malignant tumours are poorly demarcated from the surrounding normal tissue. They do not recognize normal anatomical boundaries, so they may penetrate the wall of the organ (e.g. colon), or fungate through the surface of the skin. This makes surgical resection difficult. It is necessary to remove a large margin of apparently normal tissue around the neoplasm.

MetastasesMetastasis = a tumour deposit separate from the primary tumour.Metastasis only occurs with malignant tumours. Benign tumours do not metastasise.There are 3 main pathways of spread:1. Direct seeding of body surface or cavity2. Lymphatic spread3. Haematogenous spread

Direct seeding of body surface or cavityThis can occur whenever the tumour penetrates a natural open space within the body. The most common example is in the peritoneal cavity. Metastatic deposits here are characteristic of ovarian cancer.

Lymphatic spreadThis is the most common pathway for initial spread. In many cases, regional lymph nodes can be effective barriers to further spread of the tumour, at least for a period of time. Local draining lymph nodes can undergo reactive hyperplasia due to the drainage of debris from the tumour. Therefore, large lymph nodes near a cancer do not necessarily mean that it has spread.

Haematogenous spreadTumours can more easily spread into veins than into arteries. Metastases therefore usually follow venous drainage of the tumour. The liver and lungs are most common sites of metastasis. The liver drains an extensive portion of the abdomen via the portal vein. All of the blood passes through the lungs to be oxygenated.

Characteristics Benign MalignantDifferentiation/anaplasia Well differentiated; structure may be typical of tissue of origin. Some lack of differentiation with anaplasia; structure is often atypicalRate of growth Usually progressive and slow; may come to a standstill or regress; mitotic figures are rare and normal Erratic and may be slow – rapid; mitotic figures may be numerous and abnormalLocal invasion Usually cohesive and expansile, well demarcated masses that do not invade or infilatrate surrounding normal tissues Locally invasive, infiltrating the surrounding normal tissues; sometimes may be seemingly cohesive and expansileMetastasis Absent Frequently present; the larger and more undifferentiated the primary, the more likely are metastases

NomenclatureIn general, benign tumours are named by adding the suffix –oma to the cell of origin. E.g. osteoma (benign tumour of osteoblast cells in bone)Fibroma (benign tumour of fibroblast cells)Adenoma (benign tumour of glandular epitheium)

Malignant tumour arising from mesenchymal (fibrous, non-secretory) tissue is called a sarcoma. E.g. fibrosarcoma, osteosarcoma

Malignant tumour of epithelial origin is called carcinoma. This is divided into squamous cell carcinoma and adenocarcinoma.

Names that don’t follow these rules:Melanoma – malignant carcinoma of melanocytesSeminoma – malignant carcinoma of testicular origin

Further reading: Robbins and Cotran Pathologic Basis of Disease pagers 6-9, 270-281

Anaplasia refers to undifferentiated cell growth in a malignant neoplasms (tumors). Lack of differentiation is considered a hallmark of malignancy. The term anaplasia literally means "to form backward." It implies dedifferentiation, or loss of structural and functional differentiation of normal cells. It is now known, however, that at least some cancers arise from stem cells in tissues; in these tumors failure of differentiation, rather than dedifferentiation of specialized cells, account for undifferentiated tumors.

Anaplastic cells display marked pleomorphism. The nuclei are characteristically extremely hyperchromatic (darkly stained) and large. The nuclear-to-cytoplasmic ratio may approach 1:1 instead of the normal 1:4 or 1:6. Giant cells that are considerably larger than their neighbors may be formed and possess either one enormous nucleus or several nuclei. Anaplastic nuclei are variable and bizarre in size and shape. The chromatin is coarse and clumped, and nucleoli may be of astounding size. More important, mitoses are often numerous and distinctly atypical; anarchic multiple spindles may be seen and sometimes appear as tripolar or quadripolar forms. Also, anaplastic cells usually fail to develop recognizable patterns of orientation to one another (i.e. they lose normal polarity). They may grow in sheets, with total loss of communal structures, such as gland formation or stratified squamous architecture. Anaplasia is the most extreme disturbance in cell growth encountered in the spectrum of cellular proliferations. [Kumar, Vinay, Abul Abbas, Nelson Fausto, and Richard Mitchell. Robbins Basic Pathology. 8th ed. Philadelphia: Saunders Elsevier, 2007. 176-177.]

References

ee also

*Hyperplasia
*Neoplasia
*Dysplasia
*Metaplasia